Parkinson's disease (PD) remains a major health problem for older Americans, and its pathogenesis, although not understood fully, is associated in part with some neurotoxicants. We hypothesize that cysteinylcatechols such as cysdopac, a mitochondrial toxin, accumulate in vivo over time, gradually inhibiting mitochondrial function, conferring vulnerability of nigral neurons to dopamine, and ultimately leading to neuronal degeneration. The environmental toxicant Mn2+ may accelerate this process by inhibiting mitochondria and by catalyzing cysteinylcatechol generation. To test this hypothesis, specific aim 1 attempts to determine whether Mn2+ and cysteinylcatechols such as cysdopac increase dopamine toxicity as has been demonstrated with MPP+. Then, specific aim 2 will determine whether the effects of Mn2+ and cysteinylcatechols on dopamine-associated apoptosis are associated with decreased vesicular reuptake of dopamine and increased production of reactive oxygen species (ROS). As mitochondrial dysfunction and increased ROS production may result in excitotoxicity and apoptosis, we further hypothesize that cysteinylcatechols react with the thiols of the mitochondrial transition pore, thereby mediating the mitochondrial permeability transition (PT) that initiates excitotoxicity and ultimately apoptosis of dopaminergic neurons. To test this possibility, specific aim 3 will determine whether the effects of cysteinylcatechols on dopamine-associated neuronal degeneration are related to inhibition of mitochondrial respiration and increase in mitochondrial PT. Finally, specific aim 4 will determine whether the effects of cysteinylcatechols on dopamine-associated neuronal degeneration can be blocked by antagonism of excitotoxicity.